G protein-coupled receptors (GPCRs) mediate cellular responses to an enormous diversity of signaling molecules, including hormones, neurotransmitters, and local mediators, which are as varied in structure as they are in function: the list includes proteins and small peptides, as well as amino acid and fatty acid derivatives.
Despite the chemical and functional diversity of the signaling molecules that bind to them, all of the G protein-coupled receptors whose amino acid sequences are known from DNA sequencing studies have a similar structure and are almost certainly evolutionarily related. They consist of a single polypeptide chain that threads back and forth across the lipid bilayer seven times. The members of this receptor family have conserved not only their amino acid sequence but also their functional relationship to G proteins by means of which they broadcast into the interior of the cell the message that an extracellular ligand is present.
G-protein coupled receptors are an important class of drug targets that exist on the surface membrane of all cells and are associated with a wide range of therapeutic categories, including pain control and analgesia, asthma, inflammation, obesity, cancer, cardiovascular, metabolic, viral, immunomodulator, gastrointestinal and central nervous system diseases. There are estimated to be over 1,000 GPCRs in the human genome with potential therapeutic utility. Although, GPCRs have historically been valuable drug targets, to date there are only approximately 200 well-characterized GPCRs with known ligands, of which only about half are currently targets of commercial drugs. The remaining GPCRs, for which a ligand has not been identified, are typically referred to as “orphan GPCRs”.
An orphan GPCR of particular interest is the hRUP4 receptor, hereinafter referred to as the SP9155 receptor. The SP9155 receptor also has been referred to as vc-38—1, AXOR16 and as GP103. The amino acid sequence of this receptor has been disclosed previously, for example, in several International Applications including PCT US99/19351 (WO 00/11015), PCT US99/24065 (WO 00/22131), PCT/US99/23687 (WO 00/31258), PCT/US00/16869 (WO00/78809), PCT/JP00/05684 (WO 01/16316) and PCT/JP00/09409 (WO 01/48189). However, these publications do not disclose a ligand for the SP9155 receptor. The SP9155 receptor has amino acid sequence homology to orexin A, orexin B and NPFF receptors. Orexin A and B receptors have been shown to be involved in metabolic diseases such as obesity (Shiraishi, et al., (2000) Physiol. Behav. 71:251-61; Mondal, et al., (1999) Neurosci. Lett. 273:45-48 and Dun, et al., (2000) Regul. Pept. 96:65-70). NPFF receptors have been shown to be involved pain control and analgesia (Lake, et al., (1991) Neurosci. Lett. 132:29-32; Kavaliers, et al., (1992) Peptides 13:603-607 and Dong, et al., (2001) Cell 106:619-632). Accordingly, identification of a ligand for the SP9155 receptor would be potentially useful in developing therapies for metabolic and neurological disorders.
Neuropeptides are one therapeutically important class of GPCR ligands which are used as signaling molecules in the nervous system of most organisms, including mammals. For example, RF-amide neuropeptides have been shown to have diverse functions including cardioexcitation (Greenberg, et al., (1979), Am. Zoologist 19:163-167 and Groome, et al., (1994) Biol. Bull. 186:309-318), control of muscle contraction (Bowman, et al., (1996) Peptides 17:381-387 and Franks, et al., (1994) Parasitology 108:229-236), neuromodulation in invertebrates (Brownlee, et al., (1995) Parasitology 111:379-384 and Cottrell, et al., (1983) Nature 304:638-640) as well as anti-opioid effects in vertebrates (Kavaliers, et al., (1985) Neuroendocrinology 40:533-535 and Yang, et al., (1985) Prog. Clin. Biol. Res. 192:313-322). Accordingly, the identification of the GPCRs to which neuropeptides such as RF-amides bind would also be useful in developing potential therapeutics.